Work in this laboratory has led to the structural characterization of a new pterin cofactor, molybdopterin, which is essential for the function of molybdoenzymes in man and lower organisms. The long-range goal of this project is to fully delineate the molecular biochemistry of the molybdenum cofactor, the complex of Mo and molybdopterin, in relation to human health and development. The importance of this goal is evident from the severe neurological and developmental lesions seen in patients with a genetic deficiency of the cofactor. An important issue to be addressed is whether molybdopterin, the organic component of the Mo cofactor, is totally synthesized de novo or is built up from a dietarily derived pterin precursor. A series of studies using isotopic precursors are proposed to investigate this question. The outcome of these studies could have a bearing on the nutritional requirements of the general human population. The recent discovery of a cell-permeable molybdopterin precursor has made it possible to initiate studies on the possible correction of molybdopterin deficiency in affected individuals and the possibility of increasing tissue levels of molybdopterin in normal individuals. These possibilities will be investigated using cells in culture and experimental animals. Since molybdopterin is a functional prosthetic group of sulfite oxidase, the outcome of these studies could provide mechanisms for increasing resistance to SO2 and sulfites, especially in a large number of asthmatics who display sensitivity to these agents.